Deciphering the molecular mechanisms of BPTF interactions with nucleosomes via molecular simulations.

Abstract

Transcription factors play a pivotal role in regulating DNA accessibility and gene transcription. They often have regions for recognizing and binding to post translational modifications on the long, disordered tail regions of the histone octamers found in nucleosomes. Historically these transcription factors have often been studied in vitro with short peptide sequences that mimic the histone tail, which may preclude a complete understanding of the mechanisms and potential conformational changes these proteins are subject to in vivo, where the full nucleosome is present. Here, we have used classical molecular dynamics simulations to study the transcription factor BPTF's PHD finger with and without a bromodomain alone in solution, bound to a short H3 tail peptide fragment, and bound to a full-length histone H3 in a nucleosome core particle. In addition to enhancing the accessibility of DNA for transcription, the PHD finger and bromodomain adopted different conformations in each context, which appears to be driven by electrostatic forces present in the nucleosome but absent otherwise. Together, our results suggest that transcription factor binding in the context of the full-length nucleosome is regulated by multiple factors, including interactions with nucleosomal DNA and histone proteins, which are unaccounted for in the standard histone code hypothesis.